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Clinical Study to Evaluate the Efficacy and Safety of Givinostat in Ambulant Patients With Duchenne Muscular Dystrophy

key information

study id #: NCT02851797

condition: Duchenne Muscular Dystrophy

status: recruiting

purpose:

it is a randomised, double blind, parallel group, placebo controlled study. A total of 213 male ambulant subjects will be randomised 2:1 (givinostat:placebo). Subjects will be stratified for their concomitant use of steroids in 4 strata: 1. Deflazacort daily regimen 2. Deflazacort intermittent regimen 3. Other steroids daily regimen 4. Other steroids intermittent regimen. The study duration is planned for 19 months.

study description:
Givinostat or placebo oral suspension (10 mg/mL) will be administered orally as 2 oral doses daily while the subject is in fed state, according to the child's weight.
Study drug should be permanently stopped if any of the following occur:
• severe drug-related diarrhoea;
• any drug-related Serious Adverse Event;
• QTcF >500 msec;
• platelets count =<50 x 109/L.
• white blood cells =<2.0 x 109/L
• hemoglobin =<8.0 g/dL
Study drug should be temporarily stopped if any of the following occur:
• platelets count <75 x 109/L but >50 x 109/L (the treatment should be temporarily stopped and a platelets count has to be performed and re-tested until platelets will be normalized);
• moderate or severe diarrhoea.
• white blood cell <3.0 x 109/L but >2.0 x 109/L (the treatment should be temporarily stopped and white blood cells have to be measured by 1 week and re-tested until white blood cells will be normalized);
• hemoglobin <10.0 g/dL but > 8.0 g/dL (the treatment should be temporarily stopped and hemoglobin has to be measured by 1 week and re-tested until hemoglobin will be normalized);
• Triglycerides >300 mg/dL (3.42 mmol/L) in fasting condition (the treatment should be temporarily stopped and triglycerides has to be measured every 2 weeks until triglycerides return to levels below 300mg/dL (3.42 mmol/L)
In case the study drug was temporarily stopped, the study drug can be resumed at a level 1/3 smaller than the one at which the Adverse Event leading to temporary stop occurred, once platelets and/or white blood cell and/or hemoglobin are normalized and/or triglycerides return to levels below 300 mg/dL (3.42 mmol/L) or diarrhoea is mild.
Two interim analyses are planned and will be conducted by the IDMC in order to ensure study integrity.

inclusion criteria:
• Are an ambulant male aged >=6 years at randomisation with DMD characteristic clinical symptoms or signs (e.g., proximal muscle weakness, Gowers' maneuver, elevated serum creatinine kinase level) already present at screening;
• Have DMD diagnosis confirmed by genetic testing;
• Are able to give informed assent and/or consent in writing signed by the subject and/or parent/legal guardian (according to local regulations);
• Are able to complete 2 Four Stairs Climb test (4SC) screening assessments; the results of these tests must be within ±1 second of each other;
• Have the mean of 2 screening 4SC assessments =<8 seconds;
• Have time to rise from floor between >=3 and <10 seconds at screening
• Have manual muscle testing (MMT) of quadriceps at screening Grade - 3;
• Have used systemic corticosteroids for a minimum of 6 months immediately prior to the start of study treatment, with no significant change in corticosteroids type or dosage or dosing regimen (excluding changes related to body weight change) for a minimum of 6 months immediately prior to start of study treatment and a reasonable expectation that dosage and dosing regimen will not change significantly for the duration of the study.
• Subjects must be willing to use adequate contraception.

exclusion criteria:
• Have exposure to another investigational drug within 3 months prior to the start of study treatment;
• Have exposure to idebenone within 3 months prior to the start of study treatment;
• Have exposure to any dystrophin restoration product (e.g., Ataluren, Exon skipping) within 6 months prior to the start of study treatment;
• Use of any pharmacologic treatment, other than corticosteroids, that might have had an effect on muscle strength or function within 3 months prior to the start of study treatment (e.g., growth hormone); Vitamin D, calcium, and any other supplements will be allowed as long as their intake has been stable for 3 months prior to the start of study treatment; Testosterone will also be allowed if it is used as a replacement therapy for the treatment of delayed puberty, and testosterone dose and regimen have been stable for at least 6 months and circulating testosterone levels are within the normal ranges for the subject's age;
• Have surgery that might have an effect on muscle strength or function within 3 months before study entry or planned surgery at any time during the study;
• Ankle joint contractures due to a fixed loss of >=10 degrees of dorsiflexion from plantagrade assuming a normal range of dorsiflexion of 20 degree;
• Change in contracture treatment such as serial casting, contracture control devices, night splints, stretching exercises (passive, active, self) within 3 months prior to enrollment, or expected need for such intervention during the study;
• Have presence of other clinically significant disease, which, in the Investigator's opinion, could adversely affect the safety of the subject, making it unlikely that the course of treatment or follow-up would be completed, or could impair the assessment of study results;
• Have a diagnosis of other uncontrolled neurological diseases or presence of relevant uncontrolled somatic disorders that are not related to DMD;
• Have platelets count at screening < Lower Limit of Normal (LLN);
• Have symptomatic cardiomyopathy or heart failure (New York Heart Association Class III or IV) or left ventricular ejection fraction <50% at screening;
• Have a current or history of liver disease or impairment;
• Have inadequate renal function, as defined by serum Cystatin C >2 x the upper limit of normal (ULN);
• Have Triglycerides > 300 mg/dL (3.42 mmol/L) in fasting condition at screening visit;
• Have a baseline QTcF >450 msec, or history of additional risk factors for torsades de pointes (e.g., heart failure, hypokalemia, or family history of long QT syndrome);
• Have a psychiatric illness/social situations rendering the potential subject unable to understand and comply with the muscle function tests and/or with the study protocol procedures;
• Have any known allergic reaction to givinostat or any of its excipients.
• Have any hypersensitivity to the components of study medication;
• Have a sorbitol intolerance or sorbitol malabsorption, or have the hereditary form of fructose intolerance.
• Have contraindications to MRI or MRS (e.g., claustrophobia, metal implants, or seizure disorder).